Antagonist-Elicited Cannabis Withdrawal

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Experimental Design and Methods: Experiment I: In this within-subject, randomized, double-blind, dose-escalation study, six participants receive 7 days of THC (40-120 mg/day). On Day 8, five participants receive 20 mg rimonabant; one receives placebo. If withdrawal criteria (greater than or equal to 150% or 2.5-fold increase in selected visual-analog scales) are not met in all five participants receiving rimonabant, separate groups of six are similarly treated with 40, 60 or 80 mg rimonabant, if necessary. The PI and MRP will submit all adverse events and relevant cardiovascular and scientific data to the IRB at the completion of each rimonabant dose panel. When the extramural NIDA DSMB is in place, it will review all data collected to date and develop and implement a monitoring plan, including review on completion of each dose cohort. DSMB recommendations will be reviewed by the Sponsor, Clinical Director and IRB before proceeding to the next dose cohort. In addition, if any subject has an intolerable adverse event (ie, an adverse event leading to study discontinuation) or serious adverse event in response to rimonabant on Day 8, the blind for that subject will be broken, and a report sent to the Sponsor, the extramural NIDA DSMB when in place and the IRB for discussion.

Risks and Benefits: The proposed doses of THC and rimonabant have been well tolerated in other studies. The most common side effects of oral THC are sedation, cognitive impairment, euphoria, poor coordination, tachycardia, and hypotension. Spontaneous withdrawal from cannabis is mild and medically benign. Experience with other drugs suggests that antagonist-elicited cannabis withdrawal may have an earlier onset and greater intensity than spontaneous cannabis withdrawal. There are no clinical benefits to participants. Scientific benefits are greater understanding of cannabis intoxication, tolerance, and withdrawal and of the role of rimonabant in eliciting cannabis withdrawal.

Experimental Design and Methods: Experiment I: In this within-subject, randomized, double-blind, dose-escalation study, six participants receive 7 days of THC (40-120 mg/day). On Day 8, five participants receive 20 mg rimonabant; one receives placebo. If withdrawal criteria (greater than or equal to 150% or 2.5-fold increase in selected visual-analog scales) are not met in all five participants receiving rimonabant, separate groups of six are similarly treated with 40, 60 or 80 mg rimonabant, if necessary. The PI and MRP will submit all adverse events and relevant cardiovascular and scientific data to the IRB at the completion of each rimonabant dose panel. When the extramural NIDA DSMB is in place, it will review all data collected to date and develop and implement a monitoring plan, including review on completion of each dose cohort. DSMB recommendations will be reviewed by the Sponsor, Clinical Director and IRB before proceeding to the next dose cohort. In addition, if any subject has an intolerable adverse event (ie, an adverse event leading to study discontinuation) or serious adverse event in response to rimonabant on Day 8, the blind for that subject will be broken, and a report sent to the Sponsor, the extramural NIDA DSMB when in place and the IRB for discussion.

Risks and Benefits: The proposed doses of THC and rimonabant have been well tolerated in other studies. The most common side effects of oral THC are sedation, cognitive impairment, euphoria, poor coordination, tachycardia, and hypotension. Spontaneous withdrawal from cannabis is mild and medically benign. Experience with other drugs suggests that antagonist-elicited cannabis withdrawal may have an earlier onset and greater intensity than spontaneous cannabis withdrawal. There are no clinical benefits to participants. Scientific benefits are greater understanding of cannabis intoxication, tolerance, and withdrawal and of the role of rimonabant in eliciting cannabis withdrawal.

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Layout table for eligibility information

Ages Eligible for Study:

18 Years to 45 Years (Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Eligibility Crtieria for Canabis Users

INCLUSION CRITERIA:

18 to 45 years of age;

Cannabis use of at least one year with a typical pattern of daily use for the three months prior to unit admission;

A urine sample positive for cannabinoids in the 30 days prior to study enrollment;

12-lead standard ECG and 3-minute rhythm strip without clinically relevant abnormalities and within the limits defined for the protocol in Appendix 2;

Peripheral veins suitable for repeated venipuncture and placement and maintenance of an IV catheter;

Ability to swallow capsules;

Ability to communicate well with the investigators and to comply with study requirements;

Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (beta-HCG) pregnancy test prior to study enrollment. All volunteers must use an intra-uterine device or hormonal contraception during the entire study period and for 1 month after. Women who are postmenopausal for more than 12 months or who were sterilized more than 3 months ago are not considered to have childbearing potential;

Estimated IQ greater than or equal to 85 determined by the Wechsler Abbreviated Scale of Intelligence

Right-handed (Experiment II only).

EXCLUSION CRITERIA:

History or presence of any clinically significant disease state, as detected by history, physical examination, and/or laboratory tests, that might put the subject at increased risk of adverse events or that might interfere with the absorption, distribution, metabolism, or excretion of study drugs;

Current physical dependence on any substance other than cannabis, nicotine, or caffeine;